Cyanovirin (CVN) like lectins represent a new class of anti-viral agents. The long-term goal of this proposal is to understand the molecular mechanisms and structural basis of high-affinity oligosaccharide recognition and the mode of anti-viral activity of these proteins. Lectins are well known, multifaceted carbohydrate binding proteins that specifically recognize diverse sugar structures and mediate a variety of biological processes such as cell-cell and host-pathogen interactions, serum glycoprotein turnover and innate immune responses. Although a number of lectins have been well studied, ambiguities still exist about their precise biological roles. In 1998, our laboratory solved the first structure of a cyanobacterial derived protein, cyanovirin, that exhibited potent HIV-inactivating properties. The structure revealed a novel threedimensional fold, distinct from any known lectin folds. Extensive biochemical and structural characterizations based on our initial results and primarily from our laboratory revealed that CVN's mode of action involves recognition of N-linked high-mannose oligosaccharides (Man-8 and Man-9) on gp120, resulting in viral inactivation. The structure of CVN resulted in the definition of a new structural class of lectins (CVNH family), with CVN as the class defining member. However, except for CVN, no atomic structures of any other CVNH family member have been reported and the precise structure/function relationships of all CVNH proteins remains poorly understood. We will determine structures of several representative members of this family to identify the relationship between sequence and structure conservation and establish the structural basis for high-affinity and specificity of carbohydrate recognition for this class of lectins. This will allow us to further exploit the potent anti-viral properties of this protein family, aiding in devising novel strategies for controlling the spread of AIDS, a major global health treat. Overall, we wish to establish the structural and thermodynamic basis for the cyanovirin-like lectincarbohydrate interactions as a paradigm for multivalent and multi-site binding and how these binding events relate to the unique anti-viral properties of this lectin class. Using a battery of state-of-the-art structural/functional/chemical approaches, we will undertake a vigorous investigation on a number of cyanovrin-like lectins. We believe our multidisciplinary study will not only lead to a fundamental understanding of protein-carbohydrate recognition involved in critical cellular functions, but also contribute to the development of drugs for potential therapeutic use as anti-viral agents.